Among the candidate genetic loci for differences in alcohol's toxic effects are genes encoding alcohol metabolic enzymes and thiamine-dependent enzymes including transketolase. Class III ADH (ADH5) is an unusual ADH which has an important role in the metabolism of formaldehyde (Koivusalo, 1990). This enzyme could thus play a role in methanol toxicity and in the metabolism of methanol found as a trace contaminant in alcoholic beverages. We have shown that this is the only ADH present in significant amounts in brain. We previously cloned the human class III alcohol dehydrogenase, characterized its sequence and expression and discovered a moderately informative human Sac I RFLP. We have located the ADH5 gene to the same chromosomal region in mouse and man, approximately 5 cM from the other ADH genes. We have also located several ADH pseudogenes. Utilizing the Sac I RFLP and a second more informative polymorphism identified by the PCR-SSCP method, we are investigating whether this locus is associated with the Wernicke-Korsakoff syndrome. Collaboratively with Drs. Martin and Singleton, who have cloned transketolase, we have identified a polymorphism for this gene and mapped it by genetic linkage analysis and are investigating whether it is associated with the Wernicke-Korsakoff syndrome.